Liver Transplant; Complications, NAFLD
Conditions
Keywords
Peroxisome proliferator-activated receptors, NAFLD, NASH, Post Transplant Metabolic Syndrome
Brief summary
This is a phase 2A, single center, open-label, single-arm, 24-week study to evaluate the safety, tolerability and efficacy of Saroglitazar Magnesium 4 mg in liver transplant recipients with NAFLD.
Detailed description
This is a phase 2A, single center, open-label, single-arm, 24-week study to evaluate the safety, tolerability and efficacy of Saroglitazar Magnesium 4 mg in liver transplant recipients with NAFLD. The study will be conducted over a period of up to 33 weeks and will include 5 weeks screening, a 24 week treatment period and 4 week follow-up period. The primary end point of the study is to assess the safety of Saroglitazar Magnesium 4 mg in liver transplant recipients with NAFLD over 24 weeks of treatment.
Interventions
DRUGSaroglitazar
Saroglitazar magnesium 4 mg tablet once daily (OD) in the morning 60 minutes before breakfast without food
Sponsors
Zydus Therapeutics Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Able and willing to give written informed consent. * Males or females, 18 to 75 years of age. * Patients who are at least 6 months post-transplant for nonalcoholic steatohepatitis (NASH) or cryptogenic cirrhosis thought to be secondary to NASH are eligible for enrolment. * The presence of NAFLD determined by Magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) prior to enrollment. * Patients with ≤20% variance in the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin between Visit 1 and Visit 1.1. * History of medical compliance with immunosuppression. * Female subjects of non-child bearing potential or on highly effective contraception. For male subjects with female partners of childbearing potential, willing to follow highly effective contraception measures during the study, either by the male participant or his female partner or both.
Exclusion criteria
* Pregnant or lactating females. * Patient with abnormal transaminases due to secondary intercurrent illness. * Patients with bile duct strictures. * Other causes of chronic liver disease after liver transplantation including autoimmune, viral, and alcoholic liver disease. * Graft cirrhosis as defined by: 1. Cirrhosis on historical liver biopsy. 2. Evidence of cirrhosis on imaging including portal venous collaterals. 3. Prior history of decompensated liver disease including ascites, hepatic encephalopathy or variceal bleeding. 4. Evidence of esophageal varices on prior endoscopy. * Body mass index (BMI) \<18 kg/m². * Subjects with change in body weight \>5% in the 3 months prior to enrollment. * Subjects requiring corticosteroid or anticoagulation therapy. * History of myopathies or evidence of active muscle diseases. * Unstable cardiovascular disease. * History of bladder disease and/or hematuria or has current hematuria unless due to a urinary tract infection. * Active malignancy post-liver transplantation. * History of malignancy in the past 5 years and/or active neoplasm. * History of chronic rejection of liver transplant graft. * Acute cellular rejection of liver transplant graft within the past 6 months. * Evidence of Acute cellular rejection (ACR) or chronic rejection (CR) or alternative etiologies to NAFLD. * Poorly controlled diabetes as defined by an HbA1c \>8.5% within the past 6 months. * History of excessive alcohol intake. * Subject tests positive for a urine drug screen. * Subject has a history of chronic (uncontrolled) pain.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events Assessed by CTCAE | 24 weeks | Safety measured by adverse events, vital signs, physical exams, body weight, electrocardiograms (ECGs) and lab results (including hematology, chemistry and urinalysis) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Liver Stiffness | Baseline and Week 24 | Changes in Liver stiffness as determined by MRE from baseline to end-of-treatment (EOT) Liver stiffness is a measure of a mechanical property of tissue (stiffness). This can be measured non-invasively by MR elastography, a technique that involves applying an external vibration to the abdomen and measuring the progression of shear waves through the underlying liver using MRI. |
| Frequently Sampled Intravenous Glucose Tolerance Test (Insulin Resistance Marker) | Baseline and Week 24 | Changes in frequently sampled intravenous glucose tolerance test (FSIVGTT) from baseline to EOT |
| Glycosylated Hemoglobin (Insulin Resistance Marker) | Baseline and Week 24 | Changes in glycosylated hemoglobin (HbA1c) from baseline to EOT |
| Fructosamine (Insulin Resistance Marker) | Baseline and Week 24 | Changes in fructosamine from baseline to EOT |
| Serum Liver Enzymes | Baseline and Week 24 | Changes in serum liver enzymes from baseline to EOT |
| Serum Liver Enzymes; Bilirubin | Baseline and Week 24 | Changes in bilirubin from baseline to EOT |
| Serum Lipids | Baseline and Week 24 | Changes in serum lipids from baseline to EOT |
| Small Dense Low-density Lipoprotein (Atherogenic Lipoprotein) | Baseline and Week 24 | Changes in small dense low-density lipoprotein (sdLDL) from baseline to EOT |
| LDL Size (Atherogenic Lipoprotein) | Baseline and Week 24 | Changes in LDL size from baseline to EOT |
| LDL Concentration (Atherogenic Lipoprotein) | Baseline and Week 24 | Changes in LDL concentration from baseline to EOT |
| Very Low-density Lipoprotein (Atherogenic Lipoprotein) | Baseline and Week 24 | Changes in subtypes of very low-density lipoprotein (VLDL) from baseline to EOT |
| Very Low-density Lipoprotein Chylomicron Triglyceride (Atherogenic Lipoprotein) | Baseline and Week 24 | Changes in VLDL chylomicron triglyceride from baseline to EOT |
| High-density Lipoprotein (Atherogenic Lipoprotein) | Baseline and Week 24 | Changes in high-density lipoprotein (HDL) from baseline to EOT |
| Hepatic Fat | Baseline and week 24 | Changes in hepatic fat as determined by MRI-PDFF from baseline to end-of-treatment (EOT) |
| Quality of Life (SF-36 Health Survey) | Baseline and Week 24 | Change in Quality of life score from baseline to EOT The SF-36 is a multi-purpose, short-form health survey with 36 questions. It yields an 8-scale profile of functional health and well-being scores (domains) as well as psychometrically based physical and mental health summary measures. The SF-36 taps 8 health concepts: physical functioning, bodily pain, physical role functioning, emotional role functioning, emotional well-being, social functioning, vitality, and general health perceptions. The 8 scales are further summarized to 2 distinct higher-ordered clusters: the PCS and mental composite t-score (MCS). The range for all 8 domains as well as for the composite t-scores is from 0 to 100 with 100 as best possible health status and 0 as the worst health status |
| Peak Plasma Concentration [Cmax] | PK Sampling time points: Day 1 and Week 24 visits at pre-dose (0), 0.5, 1.0, 2, 3, 4, 6, 8, 10 and 24-hour post-dose | Pharmacokinetics of Saroglitazar following first and last dose. |
| Time to Reach Peak Plasma Concentration [Tmax] | PK Sampling time points: Day 1 and Week 24 visits at pre-dose (0), 0.5, 1.0, 2, 3, 4, 6, 8, 10 and 24-hour post-dose | Pharmacokinetics of Saroglitazar following first and last dose |
| Area Under Plasma Concentration vs. Time Curve Till the Last Time Point [AUC0-t] | PK Sampling time points: Day 1 visit at pre-dose (0), 0.5, 1.0, 2, 3, 4, 6, 8, 10 and 24-hour post-dose | Pharmacokinetics of Saroglitazar |
| Area Under Plasma Concentration vs. Time Curve Extrapolated to the Infinity [AUC0-∞] | PK Sampling time points: Day 1 visit at pre-dose (0), 0.5, 1.0, 2, 3, 4, 6, 8, 10 and 24-hour post-dose | Pharmacokinetics of Saroglitazar |
| Area Under Plasma Concentration vs. Time Curve in a 24 h Dosing Interval [AUCtau] | PK Sampling time points: Day 1 and Week 24 visits at pre-dose (0), 0.5, 1.0, 2, 3, 4, 6, 8, 10 and 24-hour post-dose | Pharmacokinetics of Saroglitazar |
| Elimination Rate Constant [λz] | PK Sampling time points: Day 1 and Week 24 visits at pre-dose (0), 0.5, 1.0, 2, 3, 4, 6, 8, 10 and 24-hour post-dose | Pharmacokinetics of Saroglitazar |
| Elimination Half-life [t1/2] | PK Sampling time points: Day 1 and Week 24 visits at pre-dose (0), 0.5, 1.0, 2, 3, 4, 6, 8, 10 and 24-hour post-dose | Pharmacokinetics of Saroglitazar |
| Apparent Volume of Distribution [Vd/F] | PK Sampling time points: Day 1 (Baseline) and Week 24 visits at pre-dose (0), 0.5, 1.0, 2, 3, 4, 6, 8, 10 and 24-hour post-dose | Pharmacokinetics of Saroglitazar |
| Apparent Clearance [CL/F] | PK Sampling time points: Day 1 and Week 24 visits at pre-dose (0), 0.5, 1.0, 2, 3, 4, 6, 8, 10 and 24-hour post-dose | Pharmacokinetics of Saroglitazar |
| Minimal or Trough Plasma Concentration [Cmin] | PK Sampling time points: Week 24 visit at pre-dose (0), 0.5, 1.0, 2, 3, 4, 6, 8, 10 and 24-hour post-dose | Pharmacokinetics of Saroglitazar |
| Accumulation Index Calculated as a Ratio of AUCtau (Last Dose)/AUCtau (First Dose) | PK Sampling time points: Day 1 and Week 24 visits at pre-dose (0), 0.5, 1.0, 2, 3, 4, 6, 8, 10 and 24-hour post-dose | Pharmacokinetics of Saroglitazar |
| Fluctuation Index | PK Sampling time points: Week 24 visits at pre-dose (0), 0.5, 1.0, 2, 3, 4, 6, 8, 10 and 24-hour post-dose | Fluctuation index is the peak trough fluctuation within complete dosing interval at steady state, calculated as PTF (%) = (\[Cmax - Cmin\]/Cav ) multiplied by 100 |
| Change in Metabolic Flexibility; Time to Peak RQ | Baseline and Week 24 | Metabolic flexibility was measured via a whole room calorimeter (i.e. respiration chamber). The CO2 production and O2 consumption were recorded every minute for a total of 18 hours while study participants were in the respiration chamber on baseline and Week 24. Metabolic flexibility was quantified by measuring whole-body CO2 production relative to O2 consumption or respiratory quotient (RQ). The RQ oscillates between 0.7 and 1.0, which is indicative of either predominantly fatty acid or carbohydrate oxidation, respectively. The time to maximal carbohydrate consumption is measured by the time it takes to reach peak RQ after a standardized meal, whereas maximal carbohydrate consumption is measured at the peak of RQ vs. time curve. Next, the transition from maximal carbohydrate consumption to maximal fatty acid consumption is measured from peak RQ to lowest RQ. Finally, fasting biofuel utilization is measured in the fasting state and represents predominantly fatty acid oxidation. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Saroglitazar Magnesium 4 mg Saroglitazar Magnesium tablet once daily in the morning 60 minutes before breakfast
Saroglitazar: Saroglitazar magnesium 4 mg tablet once daily (OD) in the morning 60 minutes before breakfast without food | 20 |
| Total | 20 |
Baseline characteristics
| Characteristic | Saroglitazar Magnesium 4 mg |
|---|---|
| Age, Continuous | 58.7 years STANDARD_DEVIATION 10.96 |
| Body Mass Index | 36.8 kg/m2 STANDARD_DEVIATION 6.77 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 16 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 20 |
| other Total, other adverse events | 12 / 20 |
| serious Total, serious adverse events | 2 / 20 |
Outcome results
Primary
Number of Participants With Adverse Events Assessed by CTCAE
Safety measured by adverse events, vital signs, physical exams, body weight, electrocardiograms (ECGs) and lab results (including hematology, chemistry and urinalysis)
Time frame: 24 weeks
Population: Safety Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Saroglitazar Magnesium 4 mg | Number of Participants With Adverse Events Assessed by CTCAE | 12 Participants |
Secondary
Accumulation Index Calculated as a Ratio of AUCtau (Last Dose)/AUCtau (First Dose)
Pharmacokinetics of Saroglitazar
Time frame: PK Sampling time points: Day 1 and Week 24 visits at pre-dose (0), 0.5, 1.0, 2, 3, 4, 6, 8, 10 and 24-hour post-dose
Population: PK population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saroglitazar Magnesium 4 mg | Accumulation Index Calculated as a Ratio of AUCtau (Last Dose)/AUCtau (First Dose) | 1.134 ratio | Standard Deviation 0.203 |
Secondary
Apparent Clearance [CL/F]
Pharmacokinetics of Saroglitazar
Time frame: PK Sampling time points: Day 1 and Week 24 visits at pre-dose (0), 0.5, 1.0, 2, 3, 4, 6, 8, 10 and 24-hour post-dose
Population: PK population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saroglitazar Magnesium 4 mg | Apparent Clearance [CL/F] | Last dose (Week 24) | 6658.927 (mL/hr) | Standard Deviation 3972.114 |
| Saroglitazar Magnesium 4 mg | Apparent Clearance [CL/F] | First dose (Day 1) | 7064.331 (mL/hr) | Standard Deviation 3062.337 |
Secondary
Apparent Volume of Distribution [Vd/F]
Pharmacokinetics of Saroglitazar
Time frame: PK Sampling time points: Day 1 (Baseline) and Week 24 visits at pre-dose (0), 0.5, 1.0, 2, 3, 4, 6, 8, 10 and 24-hour post-dose
Population: PK population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saroglitazar Magnesium 4 mg | Apparent Volume of Distribution [Vd/F] | First dose | 44028.830 mL | Standard Deviation 21667.338 |
| Saroglitazar Magnesium 4 mg | Apparent Volume of Distribution [Vd/F] | Last dose | 40693.327 mL | Standard Deviation 18934.484 |
Secondary
Area Under Plasma Concentration vs. Time Curve Extrapolated to the Infinity [AUC0-∞]
Pharmacokinetics of Saroglitazar
Time frame: PK Sampling time points: Day 1 visit at pre-dose (0), 0.5, 1.0, 2, 3, 4, 6, 8, 10 and 24-hour post-dose
Population: PK population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saroglitazar Magnesium 4 mg | Area Under Plasma Concentration vs. Time Curve Extrapolated to the Infinity [AUC0-∞] | 698.354 (ng/mL)*(hr) | Standard Deviation 386.372 |
Secondary
Area Under Plasma Concentration vs. Time Curve in a 24 h Dosing Interval [AUCtau]
Pharmacokinetics of Saroglitazar
Time frame: PK Sampling time points: Day 1 and Week 24 visits at pre-dose (0), 0.5, 1.0, 2, 3, 4, 6, 8, 10 and 24-hour post-dose
Population: PK population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saroglitazar Magnesium 4 mg | Area Under Plasma Concentration vs. Time Curve in a 24 h Dosing Interval [AUCtau] | First dose (Day 1) | 689.504 (ng/mL)*(hr) | Standard Deviation 380.751 |
| Saroglitazar Magnesium 4 mg | Area Under Plasma Concentration vs. Time Curve in a 24 h Dosing Interval [AUCtau] | Last dose (Week 24) | 805.178 (ng/mL)*(hr) | Standard Deviation 513.106 |
Secondary
Area Under Plasma Concentration vs. Time Curve Till the Last Time Point [AUC0-t]
Pharmacokinetics of Saroglitazar
Time frame: PK Sampling time points: Day 1 visit at pre-dose (0), 0.5, 1.0, 2, 3, 4, 6, 8, 10 and 24-hour post-dose
Population: PK population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saroglitazar Magnesium 4 mg | Area Under Plasma Concentration vs. Time Curve Till the Last Time Point [AUC0-t] | 689.550 (ng/mL)*(hr) | Standard Deviation 380.816 |
Secondary
Change in Metabolic Flexibility; Time to Peak RQ
Metabolic flexibility was measured via a whole room calorimeter (i.e. respiration chamber). The CO2 production and O2 consumption were recorded every minute for a total of 18 hours while study participants were in the respiration chamber on baseline and Week 24. Metabolic flexibility was quantified by measuring whole-body CO2 production relative to O2 consumption or respiratory quotient (RQ). The RQ oscillates between 0.7 and 1.0, which is indicative of either predominantly fatty acid or carbohydrate oxidation, respectively. The time to maximal carbohydrate consumption is measured by the time it takes to reach peak RQ after a standardized meal, whereas maximal carbohydrate consumption is measured at the peak of RQ vs. time curve. Next, the transition from maximal carbohydrate consumption to maximal fatty acid consumption is measured from peak RQ to lowest RQ. Finally, fasting biofuel utilization is measured in the fasting state and represents predominantly fatty acid oxidation.
Time frame: Baseline and Week 24
Population: Per-Protocol Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saroglitazar Magnesium 4 mg | Change in Metabolic Flexibility; Time to Peak RQ | -53.2 minutes | Standard Deviation 78 |
Comparison: Time to peak RQp-value: 0.0193paired t-test
Secondary
Elimination Half-life [t1/2]
Pharmacokinetics of Saroglitazar
Time frame: PK Sampling time points: Day 1 and Week 24 visits at pre-dose (0), 0.5, 1.0, 2, 3, 4, 6, 8, 10 and 24-hour post-dose
Population: PK population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saroglitazar Magnesium 4 mg | Elimination Half-life [t1/2] | First dose (Day 1) | 4.199 hour | Standard Deviation 0.479 |
| Saroglitazar Magnesium 4 mg | Elimination Half-life [t1/2] | Last dose (Week 24) | 4.442 hour | Standard Deviation 0.612 |
Secondary
Elimination Rate Constant [λz]
Pharmacokinetics of Saroglitazar
Time frame: PK Sampling time points: Day 1 and Week 24 visits at pre-dose (0), 0.5, 1.0, 2, 3, 4, 6, 8, 10 and 24-hour post-dose
Population: PK population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saroglitazar Magnesium 4 mg | Elimination Rate Constant [λz] | First dose (Day 1) | 0.167 L/hour | Standard Deviation 0.02 |
| Saroglitazar Magnesium 4 mg | Elimination Rate Constant [λz] | last dose (Week 24) | 0.159 L/hour | Standard Deviation 0.024 |
Secondary
Fluctuation Index
Fluctuation index is the peak trough fluctuation within complete dosing interval at steady state, calculated as PTF (%) = (\[Cmax - Cmin\]/Cav ) multiplied by 100
Time frame: PK Sampling time points: Week 24 visits at pre-dose (0), 0.5, 1.0, 2, 3, 4, 6, 8, 10 and 24-hour post-dose
Population: PK population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saroglitazar Magnesium 4 mg | Fluctuation Index | 374.965 percentage | Standard Deviation 182.252 |
Secondary
Frequently Sampled Intravenous Glucose Tolerance Test (Insulin Resistance Marker)
Changes in frequently sampled intravenous glucose tolerance test (FSIVGTT) from baseline to EOT
Time frame: Baseline and Week 24
Population: Modified intent-to-treat population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saroglitazar Magnesium 4 mg | Frequently Sampled Intravenous Glucose Tolerance Test (Insulin Resistance Marker) | -22.68 mg/dL | Standard Deviation 29.99 |
p-value: 0.011paired t-test
Secondary
Fructosamine (Insulin Resistance Marker)
Changes in fructosamine from baseline to EOT
Time frame: Baseline and Week 24
Population: Modified intent-to-treat population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saroglitazar Magnesium 4 mg | Fructosamine (Insulin Resistance Marker) | -10.90 µmol/L | Standard Deviation 28.13 |
p-value: 0.154paired t-test
Secondary
Glycosylated Hemoglobin (Insulin Resistance Marker)
Changes in glycosylated hemoglobin (HbA1c) from baseline to EOT
Time frame: Baseline and Week 24
Population: Modified intent-to-treat population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saroglitazar Magnesium 4 mg | Glycosylated Hemoglobin (Insulin Resistance Marker) | -0.11 percentage of glycosylated hemoglobin | Standard Deviation 0.57 |
p-value: 0.454paired t-test
Secondary
Hepatic Fat
Changes in hepatic fat as determined by MRI-PDFF from baseline to end-of-treatment (EOT)
Time frame: Baseline and week 24
Population: Modified intent-to-treat population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saroglitazar Magnesium 4 mg | Hepatic Fat | -3.17 percentage of hepatic fat | Standard Deviation 5.82 |
p-value: 0.053paired t-test
Secondary
High-density Lipoprotein (Atherogenic Lipoprotein)
Changes in high-density lipoprotein (HDL) from baseline to EOT
Time frame: Baseline and Week 24
Population: Modified intent-to-treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saroglitazar Magnesium 4 mg | High-density Lipoprotein (Atherogenic Lipoprotein) | 1.82 µmol/L | Standard Deviation 4.67 |
p-value: 0.249paired t-test
Secondary
LDL Concentration (Atherogenic Lipoprotein)
Changes in LDL concentration from baseline to EOT
Time frame: Baseline and Week 24
Population: Modified intent-to-treat population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saroglitazar Magnesium 4 mg | LDL Concentration (Atherogenic Lipoprotein) | 21.70 nmol/L | Standard Deviation 155.44 |
p-value: 0.669paired t-test
Secondary
LDL Size (Atherogenic Lipoprotein)
Changes in LDL size from baseline to EOT
Time frame: Baseline and Week 24
Population: Modified intent-to-treat population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saroglitazar Magnesium 4 mg | LDL Size (Atherogenic Lipoprotein) | 0.17 nm | Standard Deviation 0.61 |
Comparison: Outcome Variable: LDL Sizep-value: 0.403paired t-test
Secondary
Liver Stiffness
Changes in Liver stiffness as determined by MRE from baseline to end-of-treatment (EOT) Liver stiffness is a measure of a mechanical property of tissue (stiffness). This can be measured non-invasively by MR elastography, a technique that involves applying an external vibration to the abdomen and measuring the progression of shear waves through the underlying liver using MRI.
Time frame: Baseline and Week 24
Population: Modified-in-to-treat population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saroglitazar Magnesium 4 mg | Liver Stiffness | 0.01 kPa | Standard Deviation 0.34 |
p-value: 0.958paired t-test
Secondary
Minimal or Trough Plasma Concentration [Cmin]
Pharmacokinetics of Saroglitazar
Time frame: PK Sampling time points: Week 24 visit at pre-dose (0), 0.5, 1.0, 2, 3, 4, 6, 8, 10 and 24-hour post-dose
Population: PK population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saroglitazar Magnesium 4 mg | Minimal or Trough Plasma Concentration [Cmin] | 2.321 ng/mL | Standard Deviation 1.994 |
Secondary
Peak Plasma Concentration [Cmax]
Pharmacokinetics of Saroglitazar following first and last dose.
Time frame: PK Sampling time points: Day 1 and Week 24 visits at pre-dose (0), 0.5, 1.0, 2, 3, 4, 6, 8, 10 and 24-hour post-dose
Population: PK population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saroglitazar Magnesium 4 mg | Peak Plasma Concentration [Cmax] | first dose (Day 1) | 174.783 ng/mL | Standard Deviation 53.673 |
| Saroglitazar Magnesium 4 mg | Peak Plasma Concentration [Cmax] | last dose (Week 24) | 115.687 ng/mL | Standard Deviation 62.68 |
Secondary
Quality of Life (SF-36 Health Survey)
Change in Quality of life score from baseline to EOT The SF-36 is a multi-purpose, short-form health survey with 36 questions. It yields an 8-scale profile of functional health and well-being scores (domains) as well as psychometrically based physical and mental health summary measures. The SF-36 taps 8 health concepts: physical functioning, bodily pain, physical role functioning, emotional role functioning, emotional well-being, social functioning, vitality, and general health perceptions. The 8 scales are further summarized to 2 distinct higher-ordered clusters: the PCS and mental composite t-score (MCS). The range for all 8 domains as well as for the composite t-scores is from 0 to 100 with 100 as best possible health status and 0 as the worst health status
Time frame: Baseline and Week 24
Population: Modified intent-to-treat population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saroglitazar Magnesium 4 mg | Quality of Life (SF-36 Health Survey) | Physical Component Score | -0.10 score on a scale | Standard Deviation 7.54 |
| Saroglitazar Magnesium 4 mg | Quality of Life (SF-36 Health Survey) | Mental Component Score | 2.63 score on a scale | Standard Deviation 8.45 |
Comparison: Outcome Variable: Physical component scorep-value: 0.96paired t-test
Comparison: Outcome Variable: Mental component scorep-value: 0.249paired t-test
Secondary
Serum Lipids
Changes in serum lipids from baseline to EOT
Time frame: Baseline and Week 24
Population: Modified Intent-to-treat population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saroglitazar Magnesium 4 mg | Serum Lipids | Change in Total Cholesterol | -5.50 mg/dL | Standard Deviation 20.74 |
| Saroglitazar Magnesium 4 mg | Serum Lipids | Change in Triglycerides | -43.20 mg/dL | Standard Deviation 47.92 |
| Saroglitazar Magnesium 4 mg | Serum Lipids | Change in Non-HDL-C | -6.20 mg/dL | Standard Deviation 17.31 |
| Saroglitazar Magnesium 4 mg | Serum Lipids | Change in HDL-C | 0.20 mg/dL | Standard Deviation 10.27 |
| Saroglitazar Magnesium 4 mg | Serum Lipids | Change in HDL-C Subclass 2 | -5.30 mg/dL | Standard Deviation 9.39 |
| Saroglitazar Magnesium 4 mg | Serum Lipids | Change in HDL-C Subclass 3 | 5.10 mg/dL | Standard Deviation 5.75 |
| Saroglitazar Magnesium 4 mg | Serum Lipids | Change in LDL-C | 2.90 mg/dL | Standard Deviation 19.4 |
| Saroglitazar Magnesium 4 mg | Serum Lipids | Change in VLDL-C | -8.50 mg/dL | Standard Deviation 9.49 |
| Saroglitazar Magnesium 4 mg | Serum Lipids | Change in VLDL concentration | -6.60 mg/dL | Standard Deviation 13.63 |
| Saroglitazar Magnesium 4 mg | Serum Lipids | Change in Small dense LDL-C | -4.29 mg/dL | Standard Deviation 5.17 |
Comparison: Outcome variable: Total Cholesterolp-value: 0.378paired t-test
Comparison: Outcome Variable: Triglyceridep-value: 0.01paired t-test
Comparison: Outcome Variable: Non-HDL-Cp-value: 0.264paired t-test
Comparison: Outcome Variable: HDL-Cp-value: 0.954paired t-test
Comparison: Outcome Variable: HDL-C Subclass 2p-value: 0.127paired t-test
Comparison: Outcome Variable: HDL-C Subclass 3p-value: 0.029paired t-test
Comparison: Outcome variable: LDL-Cp-value: 0.63paired t-test
Comparison: Outcome Variable: VLDL-Cp-value: 0.01paired t-test
Comparison: Outcome Variable: VLDL concentrationp-value: 0.16paired t-test
Comparison: Small dense LDL-Cp-value: 0.02paired t-test
Secondary
Serum Liver Enzymes
Changes in serum liver enzymes from baseline to EOT
Time frame: Baseline and Week 24
Population: Modified-intent-to-treat population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saroglitazar Magnesium 4 mg | Serum Liver Enzymes | Change in ALT | -9.10 U/L | Standard Deviation 23.23 |
| Saroglitazar Magnesium 4 mg | Serum Liver Enzymes | Change in AST | 3.90 U/L | Standard Deviation 17.56 |
| Saroglitazar Magnesium 4 mg | Serum Liver Enzymes | Change in ALP | -42.80 U/L | Standard Deviation 22.07 |
Comparison: Outcome Variable: ALTp-value: 0.125paired t-test
Comparison: Outcome Variable: ASTp-value: 0.375paired t-test
Comparison: Outcome Variable: ALPp-value: <0.001paired t-test
Secondary
Serum Liver Enzymes; Bilirubin
Changes in bilirubin from baseline to EOT
Time frame: Baseline and Week 24
Population: Modified-intent-to-treat population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saroglitazar Magnesium 4 mg | Serum Liver Enzymes; Bilirubin | -0.08 mg/dL | Standard Deviation 0.16 |
p-value: 0.054paired t-test
Secondary
Small Dense Low-density Lipoprotein (Atherogenic Lipoprotein)
Changes in small dense low-density lipoprotein (sdLDL) from baseline to EOT
Time frame: Baseline and Week 24
Population: Modified intent-to-treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saroglitazar Magnesium 4 mg | Small Dense Low-density Lipoprotein (Atherogenic Lipoprotein) | 51.40 nmol/L | Standard Deviation 248.45 |
p-value: 0.529paired t-test
Secondary
Time to Reach Peak Plasma Concentration [Tmax]
Pharmacokinetics of Saroglitazar following first and last dose
Time frame: PK Sampling time points: Day 1 and Week 24 visits at pre-dose (0), 0.5, 1.0, 2, 3, 4, 6, 8, 10 and 24-hour post-dose
Population: PK population
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Saroglitazar Magnesium 4 mg | Time to Reach Peak Plasma Concentration [Tmax] | First dose (Day 1) | 1.010 hours |
| Saroglitazar Magnesium 4 mg | Time to Reach Peak Plasma Concentration [Tmax] | Last dose (Week 24) | 2.500 hours |
Secondary
Very Low-density Lipoprotein (Atherogenic Lipoprotein)
Changes in subtypes of very low-density lipoprotein (VLDL) from baseline to EOT
Time frame: Baseline and Week 24
Population: Modified intent-to-treat population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Saroglitazar Magnesium 4 mg | Very Low-density Lipoprotein (Atherogenic Lipoprotein) | Change in VLDL chylomicron particles | -20.22 nmol/L | Standard Deviation 22.92 |
| Saroglitazar Magnesium 4 mg | Very Low-density Lipoprotein (Atherogenic Lipoprotein) | Change in Large VLDL chylomicron particles | -2.20 nmol/L | Standard Deviation 2.19 |
| Saroglitazar Magnesium 4 mg | Very Low-density Lipoprotein (Atherogenic Lipoprotein) | Change in Medium VLDL particles | -13.24 nmol/L | Standard Deviation 19.47 |
| Saroglitazar Magnesium 4 mg | Very Low-density Lipoprotein (Atherogenic Lipoprotein) | Change in Small VLDL particles | -4.79 nmol/L | Standard Deviation 14.53 |
Comparison: Outcome Variable: VLDL chylomicron particlesp-value: 0.021paired t-test
Comparison: Outcome Variable: Large VLDL chylomicron particlesp-value: 0.011paired t-test
Comparison: Outcome Variable: Medium VLDL particlesp-value: 0.06paired t-test
Comparison: Outcome Variable: Small VLDL particlesp-value: 0.324paired t-test
Secondary
Very Low-density Lipoprotein Chylomicron Triglyceride (Atherogenic Lipoprotein)
Changes in VLDL chylomicron triglyceride from baseline to EOT
Time frame: Baseline and Week 24
Population: Modified intent-to-treat population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saroglitazar Magnesium 4 mg | Very Low-density Lipoprotein Chylomicron Triglyceride (Atherogenic Lipoprotein) | -40.70 mg/dL | Standard Deviation 39.77 |
p-value: 0.01paired t-test